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Biomedical subjects

H Kirchner

Publications and source records attributed to H Kirchner.

At least 253 records · Page 14Linked to original sources
PubMed1991

alpha-Interferon and interleukin-2 in renal cell carcinoma: studies in nonhospitalized patients.

We have studied the safety, tolerance, and clinical effects of the combined administration of subcutaneous recombinant human interleukin-2 and alpha-interferon in 34 patients with metastatic renal cell carcinoma who had undergone tumor nephrectomy. Treatment courses consisted of a 2-day interleukin-2 pulse (14.4 to 18.0 million IU/m2/d), followed by 3.6 to 4.8 million IU/m2/d, 5 days per week, over 6 consecutive weeks, and alpha-interferon at 3.0 to 6.0 million U/m2, administered 2 to 3 times weekly for 6 weeks. Patients received more than 90% of the projected dose of interleukin-2 and alpha-interferon, respectively. Of 34 patients with metastatic progressive renal cell carcinoma in this study, four had complete response and six had greater than 50% reduction in tumor size (ie, partial response). There were, in addition, 13 patients with stable disease. So far, all complete responses have been durable, with a median duration of 23+ months. Clinical responses were associated with a mean peripheral blood eosinophil count of more than 1,000/microliters (P less than .05). The predominant toxicities included fever, chills, nausea, anorexia, and hypotension, and were limited to World Health Organization grades 1 and 2 in more than 80% of patients treated. No treatment-related deaths occurred. This combination of subcutaneously administered recombinant interleukin-2 and alpha-interferon has significantly reduced the side effects normally observed with high-dose intravenous recombinant interleukin-2. It can induce objective tumor regressions in patients with progressive metastatic renal cell carcinoma. Unlike the intravenous schedules developed by Rosenberg and West, which require admission to hospital, all the patients in this study were treated in an outpatient setting.

Adult↗
PubMed1990

Treatment of refractory Hodgkin's disease with high-dose cytosine arabinoside and mitoxantrone in combination. Results of a clinical phase II study of the German Hodgkin Study Group.

In the present study, the activity and side effects of high-dose cytosine arabinoside (HD-Ara-C) in combination with mitoxantrone (mitox) (HAM) was evaluated in 32 heavily pretreated patients with refractory Hodgkin's disease. Therapy consisted of HD-Ara-C 3 g/m2 every 12 hours days 1 and 2 and mitox 10 mg/m2/d days 3 to 5. In subsequent steps, HD-Ara-C was escalated to six and eight doses for 3 and 4 days, respectively, and mitox to four doses on days 2 to 5. Thirty-two patients 17 to 55 years of age entered the study. Twenty-five cases presented with extranodal disease and disseminated organ involvement and 21 revealed systemic (B) symptoms. Eighteen patients (56%) responded with five complete and 13 partial remissions, ten patients (31%) had refractory disease, and four patients died from infections during treatment-induced cytopenia. The predominant toxicity was severe myelosuppression in all patients with major infections occurring during 55% of treatment courses. Ten of the responding 18 patients underwent subsequent autologous (n = 9) or allogeneic bone marrow transplant (BMT). Seven of these cases are currently alive at 5+ to 22+ months, six of them without evidence of disease. Among the remaining eight patients not receiving BMT, three are alive at 6+ to 19+ months from the initiation of HAM, two of them in ongoing remissions of 2+ and 5+ months' duration. Two patients died from transplant-related complications and six patients succumbed to progressive disease following relapse. The median survival for all treated patients is 6.2 months. These data indicate that HAM has a significant activity in refractory Hodgkin's disease. However, the substantial side effects and the lack of an obvious superiority to alternative, less intensive regimens limits the further application of the two-drug combination in its present form. Modifications in timing and dosage and the addition of hematopoietic growth factors will be evaluated in subsequent trials.

Adolescent↗
PubMed1990

Home therapy with recombinant interleukin-2 and interferon-alpha 2b in advanced human malignancies.

The safety, tolerance, and clinical effects of a home therapy regimen of recombinant human interleukin-2 (rIL-2) and interferon-alpha 2b (IFN-alpha 2b) self injected subcutaneously have been assessed in 35 patients with advanced cancer refractory to standard therapy. 52 treatment cycles were given, each consisting of a 2-day rIL-2 pulse of 9.0 million IU/m2 every 12 h, followed by 6 weeks of rIL-2 1.8 million IU/m2 twice daily for 5 days per week and of IFN-alpha 2b 5.0 million U/m2 thrice a week. The main adverse effects were fever, chills, nausea, anorexia, and hypotension and were limited to WHO grades of severity I and II in 29 of 35 patients. No treatment-related deaths occurred. The response rates among patients with renal-cell carcinoma were similar to those reported for high-dose intravenous regimens of interleukin-2 that are toxic and have to be given in hospital.

Adult↗
PubMed1990

Cancer, cytokines, and cytotoxic cells: interleukin-2 in the immunotherapy of human neoplasms.

Modern immunotherapy of human cancer has evolved as a rapidly expanding field of clinical and experimental research. Employing the systemic application of recombinant interleukin-2 (IL-2) in humans, Rosenberg and colleagues from the National Cancer Institute reported the regression of advanced metastatic tumors in approximately 10%-30% of patients treated. The additional adoptive transfer of autologous patient-derived activated lymphocytes was performed to enhance therapeutic efficacy. While the exact mechanisms of IL-2 based immunotherapy in cancer remain unclear, it has been hypothesized that both the IL-2 activated lymphocyte and its secretory products such as interferon-gamma or tumor-necrosis factor beta may contribute to the lysis of tumor cells in vivo. Accordingly, research has been directed toward enhancing both the activation state and the specificity of IL-2 induced killer cells in humans. Based on in vitro and animal data, the retransfusion of tumor-infiltrating lymphocytes has been shown to mediate the regression of metastatic neoplasms in up to 50% of patients receiving systemic IL-2. Considerable toxicity from the use of high-dose IL-2 has prompted attempts to develop low-dose regimens which allow for the outpatient treatment of patients presenting poor prognosis. While in most clinical trials involving IL-2, patient follow-up has been short, and no or only limited data have become available from controlled prospective and randomized clinical studies, IL-2 has shown some promise in patients with metastatic renal cell cancer or malignant melanoma. Novel approaches toward the improvement of clinical efficacy of IL-2 include local (e.g., intracavitary) application or combinations with other cytokines such as interferon-alpha or cytostatic drugs.

Biological Factors↗
PubMed1990

Interferon gamma encapsulated into liposomes enhances the activity of monocytes and natural killer cells and has antiproliferative effects on tumor cells in vitro.

The effects of human interferon gamma (IFN gamma) encapsulated into liposomes were investigated in vitro. Monocytes were induced to release a cytotoxic factor with either IFN gamma encapsulated into liposomes, free IFN gamma or lipopolysaccharide (LPS). If IFN gamma was applied in the liposomal form, less IFN activity was required to stimulate monocytes. Most of the cytotoxic factor was secreted during the first 4 h of stimulation. The cytotoxic factor in supernatants from PMNLs was completely neutralized by a monospecific polyclonal antiserum to tumor necrosis factor (TNF). Combining subthreshold doses of IFN gamma liposomes or IFN gamma with lipopolysaccharide synergistically enhanced the release of TNF. In fluorescence analysis, altered expression of the class II HLA-DR antigen on LeuM3 positive monocytes was induced with IFN gamma liposomes as well as with IFN gamma. Not only monocytes but also natural killer (NK) cells were stimulated to higher cytotoxicity by IFN gamma liposomes in a dose-dependent manner. In comparison with IFN gamma, the same amount of activity was necessary for adequate stimulation of NK-cells against the K562 target cells. Furthermore, the antiproliferative effects of IFN gamma liposomes and free IFN gamma on several human tumor cell lines was compared. Among several cell lines tested, U937 and A549 turned out to be sensitive to IFN gamma, and both cell lines reacted with 50% growth inhibition at a lower amount of gamma presented by liposomes than in the free form. These data show production of IFN gamma liposomes which possess immunomodulatory and antiproliferative activity in vitro. In several of the test systems studied, liposome-encapsulated IFN gamma was more effective than free IFN gamma.

Cell Division↗
PubMed1990

Different effects of IFN gamma and IFN alpha/beta on "immediate early" gene expression of HSV-1.

The effects of interferon gamma (IFN gamma) on early steps of herpes simplex virus (Type 1; HSV-1) replication in primary cultures of splenic mouse macrophages were analyzed and compared to IFN alpha/beta. Pretreatment of macrophages with recombinant murine IFN gamma led to a dose-dependent reduction in the yield of progeny virus. Inhibition of protein synthesis was observed for HSV-1 alpha, beta and gamma-proteins. Expression of the "immediate early" (IE) gene IE3 (ICP4) was investigated in detail. Steady-state level of the RNA and transcriptional activity of the gene in IFN gamma-treated cells were comparable to control-infected cells except for a delay in their kinetics. This is in contrast to IFN alpha/beta, which leads to a stable decrease in IE3 transcripts. Since IFN gamma causes a stable decrease in the IE3 gene product ICP4, our data suggest a translational inhibition of HSV-1 IE gene expression in IFN gamma-treated macrophages. Thus, IFN gamma and IFN alpha/beta inhibit HSV-1 replication by different mechanisms which may lead to a synergistic enhancement of inhibition after combined treatment.

Animals↗
PubMed1990

Pharmacokinetic study of liposome-encapsulated human interferon-gamma after intravenous and intramuscular injection in mice.

We encapsulated human interferon-gamma (HuIFN-gamma) into liposomes and analyzed whether this preparation prevented the rapid decay of IFN-gamma in the serum of C57BL/6 mice after intravenous or intramuscular injection. Furthermore, we compared the serum decay curve of liposomal and free IFN-gamma. Whereas the intramuscular injection of IFN-gamma resulted in a serum curve with entrance compartment and subsequent biphasic elimination, intravenously injected IFN-gamma was distributed and eliminated in a biphasical manner from serum. Extremely prolonged serum titers are caused by IFN-gamma liposomes with a phospholipid composition of dimyristoylphosphatidylcholine/cholesterol/dicetylphosphate and an average particle size of 333 nm. Intramuscular injection of 2.5 mumoles liposome suspension with an antiviral activity of 4.3 x 10(3) IU/mouse resulted in longer-lasting serum titers than intravenously injected liposomes of a different charge with 2.5 mumoles and 1.2 x 10(5) IU/mouse. Liposomes after intravenous injection could be detected for up to 62 h at a titer of 20 IU/ml serum. Intramuscularly injected liposomes of the lower activity still had a titer of 30-80 IU/ml after 80 h p.i.

Animals↗
PubMed1990

Treatment of metastatic renal cell cancer patients with recombinant subcutaneous human interleukin-2 and interferon-alpha.

We treated 17 patients who had progressive metastatic renal carcinoma with a combination of subcutaneous recombinant human interleukin-2 (administered every 12 hours, at 9.0 million IU/m2 on days one and two, followed by 1.8 million IU/m2, five days per week, over six consecutive weeks) and interferon-alpha 2b (given at 5 million U/m2 three times weekly, for six consecutive weeks). Treatment courses were repeated in patients presenting with stable or regressive disease after the six weeks of combination therapy (11 of 14 evaluable). Two and three of 14 evaluable patients achieved complete and partial remissions, respectively. Toxicity of this regimen was moderate, with local inflammation of the injection sites, grade I-II (WHO) fevers, chills, malaise, nausea/vomiting, and anorexia in more than two-thirds of the patients treated.

Carcinoma, Renal Cell↗
PubMed1990

Stimulation of macrophages by endotoxin results in the reactivation of a persistent herpes simplex virus infection.

Previous work has shown that splenic macrophages derived from herpes simplex virus (HSV)-resistant C57BL/6 mice undergo a persistent HSV infection which is characterized by the continuous release of infectious virus particles from a small subpopulation of infected cells. Treatment of persistently infected macrophages for 2 weeks with lipopolysaccharide (LPS) resulted in an increase of HSV yield and in virus-induced cytopathic effects. HSV was also reactivated by treatment of macrophage cultures with lipid A or tumour necrosis factor (TNF). Like macrophages of C57BL/6 origin, cells from LPS-hyporesponsive C3H/HeJ mice could be persistently infected with HSV. These cells were resistant to LPS-induced virus reactivation. The results show that macrophages derived from C57BL/6 mice are rendered susceptible to lytic HSV infection by treatment with LPS or TNF. Thus, these substances may interfere with persistent HSV infection which can be established due to genetically controlled properties of the host.

Animals↗
PubMed1990

Induction of interleukin-6 in murine bone marrow-derived macrophages stimulated by the Mycoplasma arthritidis mitogen MAS.

Cell-free supernatant of cultures from Mycoplasma arthritidis (MAS) functions as an extremely potent T-cell mitogen for human and murine lymphocytes. The T-cell response is dependent on the presence of accessory cells, presenting the intact E2 molecule on the cell surface. Until now, pure MAS protein has not been available. We developed a new multi-step method for MAS purification. The main steps in this protocol are ammonium sulfate precipitation, anion exchange and hydroxyapatite chromatography followed by gel filtration. With this efficient protocol we obtained fractions of extremely potent mitogenic properties, the purification rate was about 5 x 10(5). Although this protease-sensitive mitogenic activity was highly enriched, we failed to detect the protein by sensitive staining methods of SDS-PAGE. In previous studies, we showed that MAS induces the synthesis of interferon gamma in human and murine lymphocyte cultures. Here we demonstrate that MAS induces interleukin-6 (IL-6) in murine bone-marrow derived macrophage cultures. Since IL-6 is also induced by endotoxin, we used C3H/HeJ mice, which are known to be LPS-nonresponders, in all our studies.

Animals↗
PubMed1990

Long-term effects of 2'-deoxycoformycin treatment on cytokine production in patients with hairy cell leukemia.

Deoxycoformycin (DCF) has been reported to cause immediate reduction and dysfunction of T lymphocytes, but the long-term effects on immune functions are still not known. As cytokine production is regulated by T helper-inducer lymphocytes and might represent a parameter for functional integrity of immunocompetent cells, we have measured the production of interleukin-2 (IL-2), tumor necrosis factor (TNF), and interferons (IFN) by peripheral mononuclear cells (PMNC) from 10 patients with hairy cell leukemia 11-24 months after end of therapy with DCF. The patients were in continuous remission at the time of study. Despite an absolute reduction in CD3+ and CD4+ lymphocytes. there were no significant differences in IL-2 or TNF release between patients and controls. Except for a significant reduction in IFN-alpha release stimulated by Newcastle disease virus (NDV), IFN productions induced by other mitogens (phytohemagglutinin, PHA; Concanavalin A, ConA; pokeweed mitogen, PWM) and viral antigens were within normal range. There was also a decrease in proliferative responsiveness to PHA, but responses to ConA, PWM, and other viral antigens were normal. In five of the patients, we have monitored closely the changes in IL-2, TNF, and IFN before, during, and after treatment and could demonstrate a rapid normalization of initially decreased IL-2 release in all cases and also of TNF if the initial production was reduced. This study shows that, even though the absolute number of T lymphocytes and helper cells are reduced in the long-term observation after DCF treatment, the capacity to produce IL-2, TNF, and IFN-gamma was within normal range. Parallel to this observation, no opportunistic infections or frequency of infectious complications occurred in these patients.

Adult↗
PubMed1990

[Knot sutures in the treatment of hemorrhoids--a conservative and modern method].

The authors describe the surgical technique and results of knot sutures in 129 patients. The principle of this operation can be compared with sclerotization. It is a relatively sparing method which can be used also in ambulatory treatment. There were no serious complications, relapses were observed in three patients.

Adolescent↗
PubMed1990

Subcutaneous interleukin-2 and interferon-alpha 2b in patients with metastatic renal cell cancer: the German outpatient experience.

A phase II clinical trial was conducted using subcutaneous recombinant human interleukin-2 (rIL-2, EuroCetus) and subcutaneous interferon-alpha 2b (rIFN-alpha 2b, Essex) in patients with advanced cancer. Safety and tolerance of this outpatient regimen were assessed in 17 patients with progressive metastatic renal carcinoma, 14 of whom were evaluable for clinical response to combined rIL-2 and rIFN-alpha 2b. In this study, rIL-2 was administered every 12 hours, at 1.5 million (Cetus) U/m2 on days 1 and 2, followed by 0.3 million U/m2 5 days per week for 6 consecutive weeks. Concomitantly, rIFN-alpha 2b was given as 5 million U/m2 three times weekly for 6 consecutive weeks. Patients presenting with stable or regressive disease after 6 weeks of rIL-2 and rIFN-alpha 2b (11 of 14) were scheduled to repeat combination therapy. After one treatment cycle, five of 14 patients presented with partial remission; two of these patients achieved complete regression of metastatic lesions. After therapy, six patients have been in stable disease for up to 8 months. toxicity of this regimen was moderate, with local inflammation of the injection sites, grade I-II (World Health Organization criteria) fevers, chills, malaise, nausea and/or vomiting, and anorexia in 70% to 100% of patients treated. After 6 weeks of rIL-2 and rIFN-alpha 2b, laboratory evidence of treatment-related hypothyroidism and hyperthyroidism was obtained in one and four patients, respectively. Immunogenicity of sc rIL-2 was mostly limited to the development of nonneutralizing antibodies that occurred in approximately 40% of patients. None of the patients exhibited antibodies specific to rIFN-alpha 2b.

Ambulatory Care↗
PubMed1990

[Rectoanal perfusion manometry--methods and results in healthy persons].

The authors elaborated a method of rectoanal perfusion manometry as part of the objective examination of the functional state of continence structures. They describe in detail the examination method and manometric equipment. In a group of 10 volunteers, 8 incontinent patients and 23 subjects after operations causing improved continence they draw attention to the great sensitivity and specificity of the examination as well as to the correlation of manometric results with results of Holschneider's evaluation by a point system. This method should be used in departments concerned with rectoanal surgery.

Adult↗
PubMed1989

Defective T-cell activation by Mycoplasma arthritidis mitogen is restored by interferon-gamma.

A mitogen derived from supernatants of Mycoplasma arthritidis (MAS) has been shown to induce both T-cell activation and the production of interferon-gamma (IFN-gamma). MAS-induced response required the presence of accessory cells and is under the genetic control associated with the major histocompatibility complex (MHC). We found that recombinant IFN-gamma restored the proliferative response to MAS mitogen in unreactive mice strains, including H-2b and H-2s haplotypes. We postulated that these T-cells fail to respond since they lack part of the I-E molecules on their accessory cells. Our data suggest that interferon-gamma may be able not only to increase the levels of Ia antigens but also to promote the appearance of MHC products that are not usually present on the cell surface. Since Ia antigens have a central role on T-cell activation, we examined the effect of the level of IFN-gamma on MAS-induced T-cell activation. We analyzed the acquisition of responsiveness to IL-2 and IL-2 activity in cells pretreated with IFN-gamma and found that both the steps of T-cell activation were restored to the MAS mitogen in the unreactive mice strains by IFN-gamma.

Animals↗